Atopic dermatitis is a chronic allergic inflammatory disease that occurs in the skin, and is characterized by the occurrence of a red rash and severe itching accompanies it when there is inflammation. When the skin is damaged by frequent scratching caused by pruritus, inflammation may worsen, symptoms may persist, and it is often more severe or more incurable even after adulthood due to a fear of side effects of a therapeutic agent. Atopic dermatitis exhibits a prevalence of 10 to 20% (children) and 1 to 3% (adults) in most countries and the number of patients worldwide is expected to increase to about 138 million people by 2022. Atopic dermatitis may be induced by various causes such as genetic factors depending on family history, environmental factors such as allergens, climate, stress and the like, allergic reactions, abnormalities of the skin barrier and the like.
The treatment of atopic dermatitis is classified into general therapy using skin moisturizers, steroid ointments, topical immunomodulators or the like, auxiliary therapy such as a skin infection treatment, prescription of antihistamines or gamma linolenic acid and the like, or selective therapy using phototherapy, systemic steroids, immunosuppressants or the like. In general therapy for patients with atopic dermatitis, a steroid-based formulation for external application was mainly used to suppress an immune reaction for drug treatment. These topical steroids which have been used as an effective therapeutic agent since 1952 are effective in mitigating an inflammatory reaction, but when topical steroids are continuously used, tolerance develops and various side effects such as atrophodermia, telangiectasia, purpura, acne, hypertrichosis, glaucoma, cataracts, pigmentation or the like occur, and thus it is difficult to apply the drug for a long time. In order to compensate for the disadvantages of these steroids, secondary drugs for treating atopic dermatitis were developed. Examples of the secondary drugs for treating atopic dermatitis include nonsteroidal immunosuppressants such as tacrolimus, pimecrolimus or the like. The drugs contribute to treating the symptoms of atopic dermatitis through a mechanism in which a small amount of the drug is applied to the skin to block the production of cytokines in immunocytes in the dermis layer of the skin and thus T cell activation is suppressed to decrease an immune reaction.
Tacrolimus, which is a nonsteroidal anti-inflammatory immunosuppressant, is a drug derived from metabolites of Streptomyces tsukubaensis. Tacrolimus has been used for various skin immune diseases related to immune reactions as well as atopic dermatitis, has less tolerance even when repeatedly used unlike steroids, and is applicable to infants or the elderly. Therefore, tacrolimus is suitable as a secondary therapeutic agent that can be applied to atopic dermatitis or other skin immune diseases.
Since tacrolimus belongs to class II of the Biopharmaceutical Classification System (BCS), which is poorly soluble in water and highly permeable, it is difficult to directly include tacrolimus in a hydrophilic gel formulation. In the case of commercial Protopic®, an ointment including tacrolimus is commercially available. However, ointments composed of lipid components exhibit significantly poor skin permeability compared to a cream formulation or gel formulation including a hydrophilic component, and this fact is directly associated with bioavailability. Therefore, a majority of studies indicate that the ointments composed of lipid components had substantially inferior drug delivery to other formulations. Also, when a patient uses it, there is a problem in which a patient feels uncomfortable because it is not washed well with water and gives a sticky feeling. In previous studies, it has been reported that commercial ointments have a significant difference in permeation rate of the drug depending on the individual and are not absorbed into the dermis but remain in the epidermis due to low permeability and, in this case, the immune environment of the epidermis is converted into an environment into which a virus can penetrate, thereby a varicella-zoster virus infection or a polyoma virus infection may be induced. In order to solve these problems, much research has been conducted on the introduction of a lipid carrier to include a poorly soluble drug such as tacrolimus having high fat solubility in a drug delivery system. There have been efforts to introduce a drug to such a lipid carrier and thus make the drug into a gel formulation, which is significantly effective in enhancing the permeability of a drug. However, it is difficult to be practically used because a manufacturing process is complicated, the cost for introducing a lipid is increased and the process therefor is complicated. Therefore, the development of a practical formulation for external application capable of enhancing skin permeability, which reduces disadvantages of an existing tacrolimus-based formulation for external dermal application, is necessary.